Division of Nephrology Translational research faculty

Fellows are introduced to translational research in a 3-step process. We initially plan for trainees who are interested in translational research to meet with our Program Faculty including Dr. Williams (Director of the Translational Research Program (TRP) at Boston Children's Hospital) and/or Co-directors of the Program. Fellows will also meet with Dr Karumanchi who will introduce them to initiatives at the Howard Hughes Medical Institute.

These initial meetings will serve to solidify the trainees' interests and to ensure that they are aware of opportunities in the local Medical Area. The TRP initiative as well as the Harvard Catalyst are also available to trainees and their involvement will results in their participation in coursework, seminars and retreats.

These center-specific activities will also introduce our trainees to their peers' common interests. The second and third steps in the structure for training will involve the selection of courses as well as the selection of a translational research mentor. The research mentor is key, and will enable the trainee to learn appropriate skills for laboratory based techniques and assays to be performed on samples collected as an integral part of the translational research study.

The choice of research mentor, and the project is discussed with Dr. Briscoe and Harmon, and a Scholarship Oversight Committee is created for the trainee. Trainees will be expected to attend one course in translational research either at Harvard Medical School, the Harvard School of Public Health, the Massachusetts General Hospital or the Clinical Investigator Training Program offered by the Massachusetts Institute of Technology. Enrollment in these courses is competitive and most demand a minimum of a 2 year commitment.

In order to enroll, a trainee must have identified a project and a laboratory mentor. The third step is the establishment of an ongoing review process, which includes a Scholarship Oversight Committee (discussed above), and regular meetings with Drs. Briscoe and/or Dr. Harmon. In addition, all trainees are expected to present their data to the entire Division once annually.

This structure and our plans for translational research training will allow our fellows to continue appropriate research beyond their fellowships, in many cases maintaining collaboration with laboratory mentors (and perhaps SOC members) who have provided early training and will serve to support the expansion of their clinical research base in our program or in new settings.

Summary: Dr Williams created the Translational Research Program (TRP) at Boston Children's Hospital (CHB) in order to stimulate and facilitate the development of preclinical and ultimately, human translational trials seeking to improve the care of children with serious diseases. In order to accomplish this, the TRP provides support for faculty-initiated pre-clinical and clinical translational research projects, in addition to ensuring adequate infrastructure to facilitate the rapid completion of these trials. The TRP will fund a cadre of investigators and support them pursue successful translational research. The TRP also provides expertise and assistance with regulatory affairs issues for TRP-sponsored individuals/projects. TRP staff with significant experience and training in regulatory affairs provide expert analysis, planning, consultation, facilitation and project management for TRP-investigators for the development of investigational new drugs. Finally, the TRP is developing a curriculum that will be available to the entire CHB community, to broaden investigators' knowledge base and ensure their success in Translational Research.

Summary: Dr. Karumanchi is a Nephrologist at the Beth Israel Deaconess Medical Center, Boston, and a clinical investigator in the Howard Hughes Medical Institute, located at Harvard Medical School. Dr. Karumanchi is known for his discovery of the cause of pre-eclampsia, and has a major interest in the role of angiogenic factors in the pathogenesis of proteinuric diseases. Dr. Karumanchi's laboratory has three major areas of study: 1) Role of angiogenesis in the pathogenesis of preeclampsia (PE): Dr. Karumanchi's laboratory identified that sFlt-1, an antagonist of circulating vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is released into the blood stream in vast excess in patients with preeclampsia. He also discovered that exogenous administration of sFlt-1 into pregnant rats reproduces the phenotype of preeclampsia, namely proteinuria, hypertension and glomerular endotheliosis (the classic lesion of preeclampsia). Further, the laboratory demonstrated that circulating sFlt-1 and PlGF levels can be used for the clinical diagnosis and the prediction of preeclampsia. Ongoing studies are testing the effects of antagonizing excess sFlt-1 with growth factors and small molecule compounds in an animal model of preeclampsia with the goal of finding novel treatment options for this disease. Additionally, the laboratory is characterizing other gene products that are elevated in preeclampsia that may serve as biomarkers for the early diagnosis. 2), Molecular mechanisms of proteinuria: Dr. Karumanchi's laboratory is evaluating mechanism(s) underlying proteinuria associated with diabetes. Preliminary microarray data generated from podocytes grown in high and normal glucose have revealed several novel targets and pathways. Urine proteomics data from diabetic patients with and without nephropathy are being analyzed in order to identify novel urine markers that predict worse renal outcomes. The laboratory is currently confirming in vitro cell culture data in diabetic rats by in-situ hybridization and is developing in vitro assays that may mimic in vivo proteinuria. 3), Renal Cancer and angiogenesis: Dr. Karumanchi discovered several novel targets that are regulated by the von Hippel-Lindau protein, including TGF beta1, TGF alpha, VEGF and AE2. Dramatic inhibition of renal tumor growth can be elicited following treatment with anti-TGF-b neutralizing antibodies, and the major mechanism appears to be an anti-angiogenic. In collaboration with the Sukhatme lab, Dr. Karumanchi is testing combination therapies with other anti-angiogenic molecules such as endostatin and restin to treat metastatic renal cancer; and he is characterizing two novel targets for VHL-associated renal cancer, identified by the laboratory.

Research Interests: Dr. Schachter's research interests focus on transplantation genomics, decision analysis in immunosuppressive drug development, and proteomic studies in pediatric nephrotic syndrome. Dr. Schachter has extensive informatics-related skills in programming, data analysis, and the use of machine-learning models.

Summary: Asher Schachter received his MD from the University of Toronto, Faculty of Medicine. He completed a residency in pediatrics at the Hospital for Sick Children in Toronto, followed by a fellowship in pediatric nephrology at Boston Children's Hospital. He also received two masters degrees from the Harvard-MIT Division of Health Sciences and Technology (Medical Science and Biomedical Informatics). He received a Sloan Industry Center Fellowship award in 2003, and was nominated to join the Society for Pediatric Research in 2005. Dr. Schachter is an Assistant Professor at Harvard Medical School, and a faculty member of the Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology. Dr. Schachter's research efforts focus on issues of Bioinformatics and artificial intelligence in pediatric renal disease. In addition, he has developed informatics models for optimizing predictive models in drug development, with the primary objective of reducing unsafe drugs, reducing post-approval adverse events, and improving the stature of children in drug development. Dr. Schachter's most recent innovative approach is aimed at predicting serious adverse events caused by FDA-approved drugs, using models that are based solely on preclinical data. This approach involves computerized modeling of drug trial data to predict rare but serious adverse events of drugs. Dr. Schachter is focused on optimizing these models, which will be made publicly accessible via the Harvard Medical School's Center for Biomedical Informatics. Another focus of Dr. Schachter's research is the molecular mechanisms underlying pediatric nephrotic syndrome (NS). Pediatric NS is the most common glomerular disease in children and the most common acquired disease causing renal failure in children. NS represents a heterogeneous group of disorders, many of which are immune mediated and drug resistant. Therefore, this population of patients provides an excellent opportunity to study drug resistance at the molecular level, and to perhaps develop novel therapies. As well, of those children with NS who require renal transplantation, many will lose their allograft to recurrence of NS, suggesting that a systemic factor is pathogenic in this most severe subgroup of patients. Dr. Schachter's research has provided some insight into the role of certain cytokines and transcription factors involved in NS. He is currently utilizing high-throughput techniques to study DNA, RNA and protein from NS patients in order to develop molecular models of NS pathogenesis and drug resistance.

Dr. Ferguson joined the clinical faculty in July, 2008. He has an interest in biomarker development for the prediction of acute renal failure and he is the local PI for two acute renal failure biomarker studies and is involved in translational research initiatives in this area. He has significant interactions with pediatric renal fellows on the clinical service.

Elizabeth Brown, MD

Dr. Brown completed training in Dr. Martin Pollak's laboratory studying the genetic basis for focal and segmental glomerulosclerosis. She is continuing to develop her effort identifying the novel gene mediating this disease.

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